Cellular and Molecular Life Sciences

, Volume 69, Issue 9, pp 1447–1473 | Cite as

Eukaryotic DNA damage checkpoint activation in response to double-strand breaks

  • Karen Finn
  • Noel Francis Lowndes
  • Muriel Grenon


Double-strand breaks (DSBs) are the most detrimental form of DNA damage. Failure to repair these cytotoxic lesions can result in genome rearrangements conducive to the development of many diseases, including cancer. The DNA damage response (DDR) ensures the rapid detection and repair of DSBs in order to maintain genome integrity. Central to the DDR are the DNA damage checkpoints. When activated by DNA damage, these sophisticated surveillance mechanisms induce transient cell cycle arrests, allowing sufficient time for DNA repair. Since the term “checkpoint” was coined over 20 years ago, our understanding of the molecular mechanisms governing the DNA damage checkpoint has advanced significantly. These pathways are highly conserved from yeast to humans. Thus, significant findings in yeast may be extrapolated to vertebrates, greatly facilitating the molecular dissection of these complex regulatory networks. This review focuses on the cellular response to DSBs in Saccharomyces cerevisiae, providing a comprehensive overview of how these signalling pathways function to orchestrate the cellular response to DNA damage and preserve genome stability in eukaryotic cells.


Cancer Checkpoint DNA damage Double-strand break Yeast Genome instability 



Ataxia telangiectasia mutated


ATM and Rad3-related


ATR interacting protein


BRCA1 carboxyl terminal


Chk1 activation domain


Cyclin-dependent kinase


Dbf4-dependent kinase


DNA damage response


DNA-dependent protein kinase catalytic subunit


Double-strand break


Gross chromosomal rearrangements


Gap phase 1


Gap phase 2


Homologous recombination


Ionising radiation




Mitotic exit network


Methyl methanesulfonate




Non-homologous end joining


Phosphoinositide 3-kinase related kinase


Post-translational modification


Ribonucleotide reductase


Replication protein A


SQ/TQ cluster domain





We apologise to authors whose publications have not been cited due to space limitations. We thank T. Weinert for critical reading of the manuscript. This work was supported by an Irish Research Council for Science, Engineering and Technology (IRCSET) grant to K.F., a Cancer Research Ireland project grant to M.G. (CR105GRE), the European Union FP6 Integrated Project “Radiosensitivity of Individuals and Susceptibility to Cancer induced by Ionising RADiations” contract number F16R-CT-2003-508842 and Science Foundation Ireland Principal Investigator award 07/IN1/B958 to N.F.L.

Conflict of interest

All co-authors have seen and agree with the contents of the manuscript. The authors certify that the submission is original work and is not under review at any other publication. The authors declare no conflict of interest.


  1. 1.
    Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362(6422):709–715PubMedCrossRefGoogle Scholar
  2. 2.
    Elledge SJ, Ciccia A (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204. doi: 10.1016/j.molcel.2010.09.019 PubMedCrossRefGoogle Scholar
  3. 3.
    Hartwell LH, Weinert TA (1989) Checkpoints: controls that ensure the order of cell cycle events. Science 246(4930):629–634PubMedCrossRefGoogle Scholar
  4. 4.
    Weinert TA, Hartwell LH (1988) The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 241(4863):317–322PubMedCrossRefGoogle Scholar
  5. 5.
    Lowndes NF, Murguia JR (2000) Sensing and responding to DNA damage. Curr Opin Genet Dev 10(1):17–25PubMedCrossRefGoogle Scholar
  6. 6.
    Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408(6811):433–439PubMedCrossRefGoogle Scholar
  7. 7.
    Bartek J, Lukas J (2007) DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol 19(2):238–245PubMedCrossRefGoogle Scholar
  8. 8.
    Harper JW, Elledge SJ (2007) The DNA damage response: ten years after. Mol Cell 28(5):739–745PubMedCrossRefGoogle Scholar
  9. 9.
    Clemenson C, Marsolier-Kergoat MC (2009) DNA damage checkpoint inactivation: adaptation and recovery. DNA Repair (Amst) 8(9):1101–1109CrossRefGoogle Scholar
  10. 10.
    Weinberg RA, Hanahan D (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi: 10.1016/j.cell.2011.02.013 PubMedCrossRefGoogle Scholar
  11. 11.
    Bartek J, Jackson SP (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071–1078. doi: 10.1038/nature08467 PubMedCrossRefGoogle Scholar
  12. 12.
    Hartwell LH, Unger MW (1977) Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division. J Cell Biol 75(2 Pt 1):422–435Google Scholar
  13. 13.
    Weinert T, Hartwell L (1989) Control of G2 delay by the rad9 gene of Saccharomyces cerevisiae. J Cell Sci Suppl 12:145–148Google Scholar
  14. 14.
    Hartwell LH, Mortimer RK, Culotti J, Culotti M (1973) Genetic control of the cell division cycle in yeast: V. genetic analysis of cdc mutants. Genetics 74(2):267–286PubMedGoogle Scholar
  15. 15.
    Lisby M, Rothstein R (2009) Choreography of recombination proteins during the DNA damage response. DNA Repair (Amst) 8(9):1068–1076CrossRefGoogle Scholar
  16. 16.
    Morgan DO (2007) The cell cycle: principles of control. Primers in biology. New Science, LondonGoogle Scholar
  17. 17.
    Futcher B (1996) Cyclins and the wiring of the yeast cell cycle. Yeast 12(16):1635–1646PubMedCrossRefGoogle Scholar
  18. 18.
    Bahler J (2005) Cell-cycle control of gene expression in budding and fission yeast. Annu Rev Genet 39:69–94PubMedCrossRefGoogle Scholar
  19. 19.
    Forsburg SL, Nurse P (1991) Cell cycle regulation in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. Annu Rev Cell Biol 7:227–256. doi: 10.1146/annurev.cb.07.110191.001303 PubMedCrossRefGoogle Scholar
  20. 20.
    Lim HH, Goh PY, Surana U (1996) Spindle pole body separation in Saccharomyces cerevisiae requires dephosphorylation of the tyrosine 19 residue of Cdc28. Mol Cell Biol 16(11):6385–6397PubMedGoogle Scholar
  21. 21.
    Yamamoto A, Guacci V, Koshland D (1996) Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s). J Cell Biol 133(1):99–110PubMedCrossRefGoogle Scholar
  22. 22.
    Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, Shokat KM, Morgan DO (2003) Targets of the cyclin-dependent kinase Cdk1. Nature 425(6960):859–864PubMedCrossRefGoogle Scholar
  23. 23.
    Holt LJ, Tuch BB, Villen J, Johnson AD, Gygi SP, Morgan DO (2009) Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325(5948):1682–1686PubMedCrossRefGoogle Scholar
  24. 24.
    Enserink JM, Kolodner RD (2010) An overview of Cdk1-controlled targets and processes. Cell Div 5:11PubMedCrossRefGoogle Scholar
  25. 25.
    Hartwell LH, Culotti J, Reid B (1970) Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci USA 66(2):352–359PubMedCrossRefGoogle Scholar
  26. 26.
    Hartwell LH, Culotti J, Pringle JR, Reid BJ (1974) Genetic control of the cell division cycle in yeast. Science 183(4120):46–51PubMedCrossRefGoogle Scholar
  27. 27.
    Fitz Gerald JN, Benjamin JM, Kron SJ (2002) Robust G1 checkpoint arrest in budding yeast: dependence on DNA damage signaling and repair. J Cell Sci 115(Pt 8):1749–1757Google Scholar
  28. 28.
    Siede W, Friedberg AS, Dianova I, Friedberg EC (1994) Characterization of G1 checkpoint control in the yeast Saccharomyces cerevisiae following exposure to DNA-damaging agents. Genetics 138(2):271–281PubMedGoogle Scholar
  29. 29.
    Siede W, Friedberg AS, Friedberg EC (1993) RAD9-dependent G1 arrest defines a second checkpoint for damaged DNA in the cell cycle of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 90(17):7985–7989PubMedCrossRefGoogle Scholar
  30. 30.
    Siede W, Allen JB, Elledge SJ, Friedberg EC (1996) The Saccharomyces cerevisiae MEC1 gene, which encodes a homolog of the human ATM gene product, is required for G1 arrest following radiation treatment. J Bacteriol 178(19):5841–5843PubMedGoogle Scholar
  31. 31.
    Longhese MP, Clerici M, Lucchini G (2003) The S-phase checkpoint and its regulation in Saccharomyces cerevisiae. Mutat Res 532(1–2):41–58PubMedGoogle Scholar
  32. 32.
    Paulovich AG, Hartwell LH (1995) A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 82(5):841–847PubMedCrossRefGoogle Scholar
  33. 33.
    Lindahl T (2000) Suppression of spontaneous mutagenesis in human cells by DNA base excision-repair. Mutat Res 462(2-3):129–135 S1383574200000247 [pii]PubMedCrossRefGoogle Scholar
  34. 34.
    Harrison JC, Haber JE (2006) Surviving the breakup: the DNA damage checkpoint. Annu Rev Genet 40:209–235PubMedCrossRefGoogle Scholar
  35. 35.
    Lovejoy CA, Cortez D (2009) Common mechanisms of PIKK regulation. DNA Repair (Amst) 8(9):1004–1008CrossRefGoogle Scholar
  36. 36.
    Critchlow SE, Jackson SP (1998) DNA end-joining: from yeast to man. Trends Biochem Sci 23(10):394–398PubMedCrossRefGoogle Scholar
  37. 37.
    Suzuki K, Kodama S, Watanabe M (1999) Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation. J Biol Chem 274(36):25571–25575PubMedCrossRefGoogle Scholar
  38. 38.
    Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548PubMedCrossRefGoogle Scholar
  39. 39.
    Dart DA, Adams KE, Akerman I, Lakin ND (2004) Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase. J Biol Chem 279(16):16433–16440. doi: 10.1074/jbc.M314212200 PubMedCrossRefGoogle Scholar
  40. 40.
    Cuadrado M, Martinez-Pastor B, Murga M, Toledo LI, Gutierrez-Martinez P, Lopez E, Fernandez-Capetillo O (2006) ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J Exp Med 203(2):297–303. doi: 10.1084/jem.20051923 PubMedCrossRefGoogle Scholar
  41. 41.
    Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8(1):37–45PubMedCrossRefGoogle Scholar
  42. 42.
    Adams KE, Medhurst AL, Dart D, Lakin ND (2006) Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex. Oncogene 25(28):3894–3904. doi: 10.1038/sj.onc.1209426 PubMedCrossRefGoogle Scholar
  43. 43.
    Stracker TH, Usui T, Petrini JH (2009) Taking the time to make important decisions: the checkpoint effector kinases Chk1 and Chk2 and the DNA damage response. DNA Repair (Amst) 8(9):1047–1054CrossRefGoogle Scholar
  44. 44.
    Sanchez Y, Bachant J, Wang H, Hu F, Liu D, Tetzlaff M, Elledge SJ (1999) Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. Science 286(5442):1166–1171PubMedCrossRefGoogle Scholar
  45. 45.
    Branzei D, Foiani M (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9(4):297–308PubMedCrossRefGoogle Scholar
  46. 46.
    Bensimon A, Aebersold R, Shiloh Y (2011) Beyond ATM: the protein kinase landscape of the DNA damage response. FEBS Lett 585(11):1625–1639. doi: 10.1016/j.febslet.2011.05.013 PubMedCrossRefGoogle Scholar
  47. 47.
    Polo SE, Jackson SP (2011) Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev 25(5):409–433. doi: 10.1101/gad.2021311 PubMedCrossRefGoogle Scholar
  48. 48.
    Bennett CB, Lewis AL, Baldwin KK, Resnick MA (1993) Lethality induced by a single site-specific double-strand break in a dispensable yeast plasmid. Proc Natl Acad Sci USA 90(12):5613–5617PubMedCrossRefGoogle Scholar
  49. 49.
    Paques F, Haber JE (1999) Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 63(2):349–404PubMedGoogle Scholar
  50. 50.
    Wu D, Topper LM, Wilson TE (2008) Recruitment and dissociation of nonhomologous end joining proteins at a DNA double-strand break in Saccharomyces cerevisiae. Genetics 178(3):1237–1249PubMedCrossRefGoogle Scholar
  51. 51.
    Martin SG, Laroche T, Suka N, Grunstein M, Gasser SM (1999) Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97(5):621–633PubMedCrossRefGoogle Scholar
  52. 52.
    Lisby M, Barlow JH, Burgess RC, Rothstein R (2004) Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118(6):699–713PubMedCrossRefGoogle Scholar
  53. 53.
    Clerici M, Mantiero D, Guerini I, Lucchini G, Longhese MP (2008) The Yku70-Yku80 complex contributes to regulate double-strand break processing and checkpoint activation during the cell cycle. EMBO Rep 9(8):810–818PubMedCrossRefGoogle Scholar
  54. 54.
    Zhang Y, Hefferin ML, Chen L, Shim EY, Tseng HM, Kwon Y, Sung P, Lee SE, Tomkinson AE (2007) Role of Dnl4-Lif1 in nonhomologous end-joining repair complex assembly and suppression of homologous recombination. Nat Struct Mol Biol 14(7):639–646PubMedCrossRefGoogle Scholar
  55. 55.
    Shim EY, Chung WH, Nicolette ML, Zhang Y, Davis M, Zhu Z, Paull TT, Ira G, Lee SE (2010) Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks. EMBO J 29(19):3370–3380. doi: 10.1038/emboj.2010.219 PubMedCrossRefGoogle Scholar
  56. 56.
    Walker JR, Corpina RA, Goldberg J (2001) Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412(6847):607–614PubMedCrossRefGoogle Scholar
  57. 57.
    Gravel S, Larrivee M, Labrecque P, Wellinger RJ (1998) Yeast Ku as a regulator of chromosomal DNA end structure. Science 280(5364):741–744PubMedCrossRefGoogle Scholar
  58. 58.
    Gottlieb TM, Jackson SP (1993) The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72(1):131–142PubMedCrossRefGoogle Scholar
  59. 59.
    Spagnolo L, Rivera-Calzada A, Pearl LH, Llorca O (2006) Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair. Mol Cell 22(4):511–519PubMedCrossRefGoogle Scholar
  60. 60.
    Weterings E, Verkaik NS, Bruggenwirth HT, Hoeijmakers JH, van Gent DC (2003) The role of DNA dependent protein kinase in synapsis of DNA ends. Nucleic Acids Res 31(24):7238–7246PubMedCrossRefGoogle Scholar
  61. 61.
    Hiom K (2010) Coping with DNA double strand breaks. DNA Repair (Amst) 9(12):1256–1263. doi: 10.1016/j.dnarep.2010.09.018 CrossRefGoogle Scholar
  62. 62.
    Smith GC, Divecha N, Lakin ND, Jackson SP (1999) DNA-dependent protein kinase and related proteins. Biochem Soc Symp 64:91–104PubMedGoogle Scholar
  63. 63.
    Chen L, Trujillo K, Ramos W, Sung P, Tomkinson AE (2001) Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes. Mol Cell 8(5):1105–1115PubMedCrossRefGoogle Scholar
  64. 64.
    Wiltzius JJ, Hohl M, Fleming JC, Petrini JH (2005) The Rad50 hook domain is a critical determinant of Mre11 complex functions. Nat Struct Mol Biol 12(5):403–407PubMedCrossRefGoogle Scholar
  65. 65.
    Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT, Carney JP, Petrini JH, Tainer JA (2002) The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. Nature 418(6897):562–566PubMedCrossRefGoogle Scholar
  66. 66.
    Lammens K, Bemeleit DJ, Mockel C, Clausing E, Schele A, Hartung S, Schiller CB, Lucas M, Angermuller C, Soding J, Strasser K, Hopfner KP (2011) The Mre11: Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair. Cell 145(1):54–66. doi: 10.1016/j.cell.2011.02.038 PubMedCrossRefGoogle Scholar
  67. 67.
    Frank-Vaillant M, Marcand S (2002) Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol Cell 10(5):1189–1199PubMedCrossRefGoogle Scholar
  68. 68.
    Barlow JH, Lisby M, Rothstein R (2008) Differential regulation of the cellular response to DNA double-strand breaks in G1. Mol Cell 30(1):73–85PubMedCrossRefGoogle Scholar
  69. 69.
    Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, Liberi G, Bressan D, Wan L, Hollingsworth NM, Haber JE, Foiani M (2004) DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431(7011):1011–1017PubMedCrossRefGoogle Scholar
  70. 70.
    Aylon Y, Liefshitz B, Kupiec M (2004) The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle. EMBO J 23(24):4868–4875PubMedCrossRefGoogle Scholar
  71. 71.
    Huertas P, Cortes-Ledesma F, Sartori AA, Aguilera A, Jackson SP (2008) CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455(7213):689–692PubMedCrossRefGoogle Scholar
  72. 72.
    Kadyk LC, Hartwell LH (1993) Replication-dependent sister chromatid recombination in rad1 mutants of Saccharomyces cerevisiae. Genetics 133(3):469–487PubMedGoogle Scholar
  73. 73.
    Lieber MR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:181–211. doi: 10.1146/annurev.biochem.052308.093131 PubMedCrossRefGoogle Scholar
  74. 74.
    Heyer WD, Ehmsen KT, Liu J (2010) Regulation of homologous recombination in eukaryotes. Annu Rev Genet 44:113–139. doi: 10.1146/annurev-genet-051710-150955 PubMedCrossRefGoogle Scholar
  75. 75.
    Rupnik A, Lowndes NF, Grenon M (2010) MRN and the race to the break. Chromosoma 119(2):115–135. doi: 10.1007/s00412-009-0242-4 PubMedCrossRefGoogle Scholar
  76. 76.
    Nakada D, Matsumoto K, Sugimoto K (2003) ATM-related Tel1 associates with double-strand breaks through an Xrs2-dependent mechanism. Genes Dev 17(16):1957–1962PubMedCrossRefGoogle Scholar
  77. 77.
    Usui T, Ogawa H, Petrini JH (2001) A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Mol Cell 7(6):1255–1266PubMedCrossRefGoogle Scholar
  78. 78.
    D’Amours D, Jackson SP (2001) The yeast Xrs2 complex functions in S phase checkpoint regulation. Genes Dev 15(17):2238–2249PubMedCrossRefGoogle Scholar
  79. 79.
    Grenon M, Gilbert C, Lowndes NF (2001) Checkpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex. Nat Cell Biol 3(9):844–847PubMedCrossRefGoogle Scholar
  80. 80.
    Mantiero D, Clerici M, Lucchini G, Longhese MP (2007) Dual role for Saccharomyces cerevisiae Tel1 in the checkpoint response to double-strand breaks. EMBO Rep 8(4):380–387PubMedCrossRefGoogle Scholar
  81. 81.
    Vialard JE, Gilbert CS, Green CM, Lowndes NF (1998) The budding yeast Rad9 checkpoint protein is subjected to Mec1/Tel1-dependent hyperphosphorylation and interacts with Rad53 after DNA damage. EMBO J 17(19):5679–5688PubMedCrossRefGoogle Scholar
  82. 82.
    Morrow DM, Tagle DA, Shiloh Y, Collins FS, Hieter P (1995) TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82(5):831–840PubMedCrossRefGoogle Scholar
  83. 83.
    Sanchez Y, Desany BA, Jones WJ, Liu Q, Wang B, Elledge SJ (1996) Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271(5247):357–360PubMedCrossRefGoogle Scholar
  84. 84.
    Fukunaga K, Kwon Y, Sung P, Sugimoto K (2011) Activation of protein kinase Tel1 through recognition of protein-bound DNA ends. Mol Cell Biol 31(10):1959–1971. doi: 10.1128/MCB.05157-11 PubMedCrossRefGoogle Scholar
  85. 85.
    Baroni E, Viscardi V, Cartagena-Lirola H, Lucchini G, Longhese MP (2004) The functions of budding yeast Sae2 in the DNA damage response require Mec1- and Tel1-dependent phosphorylation. Mol Cell Biol 24(10):4151–4165PubMedCrossRefGoogle Scholar
  86. 86.
    Clerici M, Mantiero D, Lucchini G, Longhese MP (2006) The Saccharomyces cerevisiae Sae2 protein negatively regulates DNA damage checkpoint signalling. EMBO Rep 7(2):212–218PubMedCrossRefGoogle Scholar
  87. 87.
    Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506. doi: 10.1038/nature01368 PubMedCrossRefGoogle Scholar
  88. 88.
    Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434(7033):605–611PubMedCrossRefGoogle Scholar
  89. 89.
    You Z, Chahwan C, Bailis J, Hunter T, Russell P (2005) ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol Cell Biol 25(13):5363–5379PubMedCrossRefGoogle Scholar
  90. 90.
    Lee JH, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308(5721):551–554. doi: 10.1126/science.1108297 PubMedCrossRefGoogle Scholar
  91. 91.
    Jazayeri A, Balestrini A, Garner E, Haber JE, Costanzo V (2008) Mre11-Rad50-Nbs1-dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity. EMBO J 27(14):1953–1962. doi: 10.1038/emboj.2008.128 PubMedCrossRefGoogle Scholar
  92. 92.
    Shiotani B, Zou L (2009) Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell 33(5):547–558. doi: 10.1016/j.molcel.2009.01.024 PubMedCrossRefGoogle Scholar
  93. 93.
    Sun Y, Xu Y, Roy K, Price BD (2007) DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol Cell Biol 27(24):8502–8509. doi: 10.1128/MCB.01382-07 PubMedCrossRefGoogle Scholar
  94. 94.
    Sun Y, Jiang X, Chen S, Fernandes N, Price BD (2005) A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci USA 102(37):13182–13187. doi: 10.1073/pnas.0504211102 PubMedCrossRefGoogle Scholar
  95. 95.
    Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276(45):42462–42467PubMedCrossRefGoogle Scholar
  96. 96.
    Downs JA, Lowndes NF, Jackson SP (2000) A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature 408(6815):1001–1004PubMedCrossRefGoogle Scholar
  97. 97.
    Stiff T, O’Driscoll M, Rief N, Iwabuchi K, Lobrich M, Jeggo PA (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 64(7):2390–2396PubMedCrossRefGoogle Scholar
  98. 98.
    Ward IM, Chen J (2001) Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem 276(51):47759–47762PubMedGoogle Scholar
  99. 99.
    Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE, Lichten M (2004) Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr Biol 14(19):1703–1711PubMedCrossRefGoogle Scholar
  100. 100.
    Downs JA, Nussenzweig MC, Nussenzweig A (2007) Chromatin dynamics and the preservation of genetic information. Nature 447(7147):951–958PubMedCrossRefGoogle Scholar
  101. 101.
    Costelloe T, Fitzgerald J, Murphy NJ, Flaus A, Lowndes NF (2006) Chromatin modulation and the DNA damage response. Exp Cell Res 312(14):2677–2686PubMedCrossRefGoogle Scholar
  102. 102.
    Rossetto D, Truman AW, Kron SJ, Cote J (2010) Epigenetic modifications in double-strand break DNA damage signaling and repair. Clin Cancer Res 16(18):4543–4552. doi: 10.1158/1078-0432.CCR-10-0513 PubMedCrossRefGoogle Scholar
  103. 103.
    Xu Y, Price BD (2011) Chromatin dynamics and the repair of DNA double strand breaks. Cell Cycle 10(2):261–267PubMedCrossRefGoogle Scholar
  104. 104.
    Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273(10):5858–5868PubMedCrossRefGoogle Scholar
  105. 105.
    Rogakou EP, Boon C, Redon C, Bonner WM (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146(5):905–916PubMedCrossRefGoogle Scholar
  106. 106.
    Redon C, Pilch DR, Rogakou EP, Orr AH, Lowndes NF, Bonner WM (2003) Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint-blind DNA damage. EMBO Rep 4(7):1–7CrossRefGoogle Scholar
  107. 107.
    Toh GW, O’Shaughnessy AM, Jimeno S, Dobbie IM, Grenon M, Maffini S, O’Rorke A, Lowndes NF (2006) Histone H2A phosphorylation and H3 methylation are required for a novel Rad9 DSB repair function following checkpoint activation. DNA Repair (Amst) 5:693–703Google Scholar
  108. 108.
    Hammet A, Magill C, Heierhorst J, Jackson SP (2007) Rad9 BRCT domain interaction with phosphorylated H2AX regulates the G1 checkpoint in budding yeast. EMBO Rep 8(9):851–857PubMedCrossRefGoogle Scholar
  109. 109.
    Javaheri A, Wysocki R, Jobin-Robitaille O, Altaf M, Cote J, Kron SJ (2006) Yeast G1 DNA damage checkpoint regulation by H2A phosphorylation is independent of chromatin remodeling. Proc Natl Acad Sci USA 103(37):13771–13776PubMedCrossRefGoogle Scholar
  110. 110.
    Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW (2003) Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114(3):359–370PubMedCrossRefGoogle Scholar
  111. 111.
    Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A (2003) H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114(3):371–383PubMedCrossRefGoogle Scholar
  112. 112.
    Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A (2002) Genomic instability in mice lacking histone H2AX. Science 296(5569):922–927PubMedCrossRefGoogle Scholar
  113. 113.
    Xie A, Puget N, Shim I, Odate S, Jarzyna I, Bassing CH, Alt FW, Scully R (2004) Control of sister chromatid recombination by histone H2AX. Mol Cell 16(6):1017–1025PubMedCrossRefGoogle Scholar
  114. 114.
    Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A (2002) DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol 4(12):993–997PubMedCrossRefGoogle Scholar
  115. 115.
    van Attikum H, Gasser SM (2009) Crosstalk between histone modifications during the DNA damage response. Trends Cell Biol 19(5):207–217PubMedCrossRefGoogle Scholar
  116. 116.
    Huertas D, Sendra R, Munoz P (2009) Chromatin dynamics coupled to DNA repair. Epigenetics 4(1):31–42PubMedCrossRefGoogle Scholar
  117. 117.
    Soutoglou E, Misteli T (2008) Activation of the cellular DNA damage response in the absence of DNA lesions. Science 320(5882):1507–1510PubMedCrossRefGoogle Scholar
  118. 118.
    Bonilla CY, Melo JA, Toczyski DP (2008) Colocalization of sensors is sufficient to activate the DNA damage checkpoint in the absence of damage. Mol Cell 30(3):267–276PubMedCrossRefGoogle Scholar
  119. 119.
    Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Bonner WM, Nussenzweig A (2003) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 5(7):675–679PubMedCrossRefGoogle Scholar
  120. 120.
    Lou Z, Minter-Dykhouse K, Franco S, Gostissa M, Rivera MA, Celeste A, Manis JP, van Deursen J, Nussenzweig A, Paull TT, Alt FW, Chen J (2006) MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell 21(2):187–200PubMedCrossRefGoogle Scholar
  121. 121.
    Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP (2005) MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123(7):1213–1226PubMedCrossRefGoogle Scholar
  122. 122.
    Al-Hakim A, Escribano-Diaz C, Landry MC, O’Donnell L, Panier S, Szilard RK, Durocher D (2010) The ubiquitous role of ubiquitin in the DNA damage response. DNA Repair (Amst) 9(12):1229–1240. doi: 10.1016/j.dnarep.2010.09.011 CrossRefGoogle Scholar
  123. 123.
    Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J (2007) RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131(5):887–900PubMedCrossRefGoogle Scholar
  124. 124.
    Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J (2007) RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131(5):901–914PubMedCrossRefGoogle Scholar
  125. 125.
    Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD, Panier S, Mendez M, Wildenhain J, Thomson TM, Pelletier L, Jackson SP, Durocher D (2007) Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318(5856):1637–1640PubMedCrossRefGoogle Scholar
  126. 126.
    Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D (2009) The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136(3):420–434PubMedCrossRefGoogle Scholar
  127. 127.
    Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen DH, Pepperkok R, Ellenberg J, Panier S, Durocher D, Bartek J, Lukas J, Lukas C (2009) RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136(3):435–446PubMedCrossRefGoogle Scholar
  128. 128.
    Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y, Ogata H, Ohta T (2001) The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J Biol Chem 276(18):14537–14540PubMedCrossRefGoogle Scholar
  129. 129.
    Bekker-Jensen S, Rendtlew Danielsen J, Fugger K, Gromova I, Nerstedt A, Lukas C, Bartek J, Lukas J, Mailand N (2010) HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nat Cell Biol 12(1):80–86; sup pp 81–12. doi: 10.1038/ncb2008 Google Scholar
  130. 130.
    Watanabe K, Iwabuchi K, Sun J, Tsuji Y, Tani T, Tokunaga K, Date T, Hashimoto M, Yamaizumi M, Tateishi S (2009) RAD18 promotes DNA double-strand break repair during G1 phase through chromatin retention of 53BP1. Nucleic Acids Res 37(7):2176–2193. doi: 10.1093/nar/gkp082 PubMedCrossRefGoogle Scholar
  131. 131.
    Mimitou EP, Symington LS (2008) Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455(7214):770–774PubMedCrossRefGoogle Scholar
  132. 132.
    Zhu Z, Chung WH, Shim EY, Lee SE, Ira G (2008) Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134(6):981–994PubMedCrossRefGoogle Scholar
  133. 133.
    Lobachev KS, Gordenin DA, Resnick MA (2002) The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell 108(2):183–193PubMedCrossRefGoogle Scholar
  134. 134.
    Deng C, Brown JA, You D, Brown JM (2005) Multiple endonucleases function to repair covalent topoisomerase I complexes in Saccharomyces cerevisiae. Genetics 170(2):591–600PubMedCrossRefGoogle Scholar
  135. 135.
    Lengsfeld BM, Rattray AJ, Bhaskara V, Ghirlando R, Paull TT (2007) Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Mol Cell 28(4):638–651PubMedCrossRefGoogle Scholar
  136. 136.
    Clerici M, Mantiero D, Lucchini G, Longhese MP (2005) The Saccharomyces cerevisiae Sae2 protein promotes resection and bridging of double strand break ends. J Biol Chem 280(46):38631–38638PubMedCrossRefGoogle Scholar
  137. 137.
    Dynan WS, Yoo S (1998) Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res 26(7):1551–1559PubMedCrossRefGoogle Scholar
  138. 138.
    Mimitou EP, Symington LS (2011) DNA end resection-Unraveling the tail. DNA Repair (Amst). doi: 10.1016/j.dnarep.2010.12.004
  139. 139.
    Gravel S, Chapman JR, Magill C, Jackson SP (2008) DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev 22(20):2767–2772PubMedCrossRefGoogle Scholar
  140. 140.
    Nicolette ML, Lee K, Guo Z, Rani M, Chow JM, Lee SE, Paull TT (2010) Mre11-Rad50-Xrs2 and Sae2 promote 5′ strand resection of DNA double-strand breaks. Nat Struct Mol Biol 17(12):1478–1485. doi: 10.1038/nsmb.1957 PubMedCrossRefGoogle Scholar
  141. 141.
    Mimitou EP, Symington LS (2010) Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO J 29(19):3358–3369. doi: 10.1038/emboj.2010.193 PubMedCrossRefGoogle Scholar
  142. 142.
    Engels K, Giannattasio M, Muzi-Falconi M, Lopes M, Ferrari S (2011) 14-3-3 Proteins regulate exonuclease 1-dependent processing of stalled replication forks. PLoS Genet 7(4):e1001367. doi: 10.1371/journal.pgen.1001367
  143. 143.
    Niu H, Chung WH, Zhu Z, Kwon Y, Zhao W, Chi P, Prakash R, Seong C, Liu D, Lu L, Ira G, Sung P (2010) Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae. Nature 467(7311):108–111. doi: 10.1038/nature09318 PubMedCrossRefGoogle Scholar
  144. 144.
    Cejka P, Cannavo E, Polaczek P, Masuda-Sasa T, Pokharel S, Campbell JL, Kowalczykowski SC (2010) DNA end resection by Dna2-Sgs1-RPA and its stimulation by Top3-Rmi1 and Mre11-Rad50-Xrs2. Nature 467(7311):112–116. doi: 10.1038/nature09355 PubMedCrossRefGoogle Scholar
  145. 145.
    Nimonkar AV, Genschel J, Kinoshita E, Polaczek P, Campbell JL, Wyman C, Modrich P, Kowalczykowski SC (2011) BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev 25(4):350–362. doi: 10.1101/gad.2003811 PubMedCrossRefGoogle Scholar
  146. 146.
    Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC (2008) Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair. Proc Natl Acad Sci USA 105(44):16906–16911. doi: 10.1073/pnas.0809380105 PubMedCrossRefGoogle Scholar
  147. 147.
    Niu H, Raynard S, Sung P (2009) Multiplicity of DNA end resection machineries in chromosome break repair. Genes Dev 23(13):1481–1486PubMedCrossRefGoogle Scholar
  148. 148.
    Longhese MP, Bonetti D, Manfrini N, Clerici M (2010) Mechanisms and regulation of DNA end resection. EMBO J 29(17):2864–2874. doi: 10.1038/emboj.2010.165 PubMedCrossRefGoogle Scholar
  149. 149.
    Zierhut C, Diffley JF (2008) Break dosage, cell cycle stage and DNA replication influence DNA double strand break response. EMBO J 27(13):1875–1885. doi: 10.1038/emboj.2008.111 PubMedCrossRefGoogle Scholar
  150. 150.
    Chen L, Nievera CJ, Lee AY, Wu X (2008) Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem 283(12):7713–7720Google Scholar
  151. 151.
    Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J, Jackson SP (2007) Human CtIP promotes DNA end resection. Nature 450(7169):509–514PubMedCrossRefGoogle Scholar
  152. 152.
    Yu X, Chen J (2004) DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol Cell Biol 24(21):9478–9486PubMedCrossRefGoogle Scholar
  153. 153.
    Yu X, Fu S, Lai M, Baer R, Chen J (2006) BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev 20(13):1721–1726PubMedCrossRefGoogle Scholar
  154. 154.
    Yun MH, Hiom K (2009) CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459(7245):460–463PubMedCrossRefGoogle Scholar
  155. 155.
    Huertas P, Jackson SP (2009) Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J Biol Chem 284(14):9558–9565PubMedCrossRefGoogle Scholar
  156. 156.
    Chen X, Niu H, Chung WH, Zhu Z, Papusha A, Shim EY, Lee SE, Sung P, Ira G (2011) Cell cycle regulation of DNA double-strand break end resection by Cdk1-dependent Dna2 phosphorylation. Nat Struct Mol Biol 18(9):1015–1019. doi: 10.1038/nsmb.2105 PubMedCrossRefGoogle Scholar
  157. 157.
    Lee SE, Moore JK, Holmes A, Umezu K, Kolodner RD, Haber JE (1998) Saccharomyces Ku70, mre11/rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94(3):399–409PubMedCrossRefGoogle Scholar
  158. 158.
    Lydall D, Weinert T (1995) Yeast checkpoint genes in DNA damage processing: implications for repair and arrest. Science 270(5241):1488–1491PubMedCrossRefGoogle Scholar
  159. 159.
    Lazzaro F, Sapountzi V, Granata M, Pellicioli A, Vaze M, Haber JE, Plevani P, Lydall D, Muzi-Falconi M (2008) Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeres. EMBO J 27(10):1502–1512PubMedGoogle Scholar
  160. 160.
    Postow L (2011) Destroying the ring: Freeing DNA from Ku with ubiquitin. FEBS Lett 585(18):2876–2882. doi: 10.1016/j.febslet.2011.05.046 PubMedCrossRefGoogle Scholar
  161. 161.
    Couto CA, Wang HY, Green JC, Kiely R, Siddaway R, Borer C, Pears CJ, Lakin ND (2011) PARP regulates nonhomologous end joining through retention of Ku at double-strand breaks. J Cell Biol 194(3):367–375. doi: 10.1083/jcb.201012132 PubMedCrossRefGoogle Scholar
  162. 162.
    Paciotti V, Clerici M, Lucchini G, Longhese MP (2000) The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast. Genes Dev 14(16):2046–2059Google Scholar
  163. 163.
    Majka J, Niedziela-Majka A, Burgers PM (2006) The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint. Mol Cell 24(6):891–901PubMedCrossRefGoogle Scholar
  164. 164.
    Cortez D, Guntuku S, Qin J, Elledge SJ (2001) ATR and ATRIP: partners in checkpoint signaling. Science 294(5547):1713–1716PubMedCrossRefGoogle Scholar
  165. 165.
    Rouse J, Jackson SP (2002) Lcd1p recruits Mec1p to DNA lesions in vitro and in vivo. Mol Cell 9(4):857–869PubMedCrossRefGoogle Scholar
  166. 166.
    Kondo T, Wakayama T, Naiki T, Matsumoto K, Sugimoto K (2001) Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science 294(5543):867–870PubMedCrossRefGoogle Scholar
  167. 167.
    Melo JA, Cohen J, Toczyski DP (2001) Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev 15(21):2809–2821PubMedGoogle Scholar
  168. 168.
    Itakura E, Takai KK, Umeda K, Kimura M, Ohsumi M, Tamai K, Matsuura A (2004) Amino-terminal domain of ATRIP contributes to intranuclear relocation of the ATR-ATRIP complex following DNA damage. FEBS Lett 577(1–2):289–293PubMedCrossRefGoogle Scholar
  169. 169.
    Wu X, Shell SM, Zou Y (2005) Interaction and colocalization of Rad9/Rad1/Hus1 checkpoint complex with replication protein A in human cells. Oncogene 24(29):4728–4735PubMedCrossRefGoogle Scholar
  170. 170.
    Dore AS, Kilkenny ML, Rzechorzek NJ, Pearl LH (2009) Crystal structure of the rad9-rad1-hus1 DNA damage checkpoint complex–implications for clamp loading and regulation. Mol Cell 34(6):735–745PubMedCrossRefGoogle Scholar
  171. 171.
    Sohn SY, Cho Y (2009) Crystal structure of the human rad9-hus1-rad1 clamp. J Mol Biol 390(3):490–502PubMedCrossRefGoogle Scholar
  172. 172.
    Green CM, Erdjument-Bromage H, Tempst P, Lowndes NF (2000) A novel Rad24 checkpoint protein complex closely related to replication factor C. Curr Biol 10(1):39–42PubMedCrossRefGoogle Scholar
  173. 173.
    Majka J, Burgers PM (2003) Yeast Rad17/Mec3/Ddc1: a sliding clamp for the DNA damage checkpoint. Proc Natl Acad Sci USA 100(5):2249–2254PubMedCrossRefGoogle Scholar
  174. 174.
    Majka J, Binz SK, Wold MS, Burgers PM (2006) Replication protein A directs loading of the DNA damage checkpoint clamp to 5′-DNA junctions. J Biol Chem 281(38):27855–27861PubMedCrossRefGoogle Scholar
  175. 175.
    Ellison V, Stillman B (2003) Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5′ recessed DNA. PLoS Biol 1(2):E33PubMedCrossRefGoogle Scholar
  176. 176.
    Cimprich KA (2007) Probing ATR activation with model DNA templates. Cell Cycle 6(19):2348–2354PubMedCrossRefGoogle Scholar
  177. 177.
    Navadgi-Patil VM, Burgers PM (2009) The unstructured C-terminal tail of the 9–1-1 clamp subunit Ddc1 activates Mec1/ATR via two distinct mechanisms. Mol Cell 36(5):743–753PubMedCrossRefGoogle Scholar
  178. 178.
    Paciotti V, Lucchini G, Plevani P, Longhese MP (1998) Mec1p is essential for phosphorylation of the yeast DNA damage checkpoint protein Ddc1p, which physically interacts with Mec3p. EMBO J 17(14):4199–4209PubMedCrossRefGoogle Scholar
  179. 179.
    de la Torre-Ruiz MA, Green CM, Lowndes NF (1998) RAD9 and RAD24 define two additive, interacting branches of the DNA damage checkpoint pathway in budding yeast normally required for Rad53 modification and activation. EMBO J 17(9):2687–2698PubMedCrossRefGoogle Scholar
  180. 180.
    Brush GS, Kelly TJ (2000) Phosphorylation of the replication protein A large subunit in the Saccharomyces cerevisiae checkpoint response. Nucleic Acids Res 28(19):3725–3732PubMedCrossRefGoogle Scholar
  181. 181.
    Navadgi-Patil VM, Burgers PM (2011) Cell-cycle-specific activators of the Mec1/ATR checkpoint kinase. Biochem Soc Trans 39(2):600–605. doi: 10.1042/BST0390600 PubMedCrossRefGoogle Scholar
  182. 182.
    Navadgi-Patil VM, Burgers PM (2009) A tale of two tails: activation of DNA damage checkpoint kinase Mec1/ATR by the 9–1-1 clamp and by Dpb11/TopBP1. DNA Repair (Amst) 8(9):996–1003CrossRefGoogle Scholar
  183. 183.
    Lee J, Kumagai A, Dunphy WG (2007) The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J Biol Chem 282(38):28036–28044PubMedCrossRefGoogle Scholar
  184. 184.
    Delacroix S, Wagner JM, Kobayashi M, Yamamoto K, Karnitz LM (2007) The Rad9-Hus1-Rad1 (9–1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev 21(12):1472–1477PubMedCrossRefGoogle Scholar
  185. 185.
    Takeishi Y, Ohashi E, Ogawa K, Masai H, Obuse C, Tsurimoto T (2010) Casein kinase 2-dependent phosphorylation of human Rad9 mediates the interaction between human Rad9-Hus1-Rad1 complex and TopBP1. Genes Cells 15(7):761–771. doi: 10.1111/j.1365-2443.2010.01418.x PubMedCrossRefGoogle Scholar
  186. 186.
    Rappas M, Oliver AW, Pearl LH (2011) Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1. Nucleic Acids Res 39(1):313–324. doi: 10.1093/nar/gkq743 PubMedCrossRefGoogle Scholar
  187. 187.
    Kumagai A, Lee J, Yoo HY, Dunphy WG (2006) TopBP1 activates the ATR-ATRIP complex. Cell 124(5):943–955PubMedCrossRefGoogle Scholar
  188. 188.
    Mordes DA, Glick GG, Zhao R, Cortez D (2008) TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev 22(11):1478–1489PubMedCrossRefGoogle Scholar
  189. 189.
    Mordes DA, Nam EA, Cortez D (2008) Dpb11 activates the Mec1-Ddc2 complex. Proc Natl Acad Sci USA 105(48):18730–18734PubMedCrossRefGoogle Scholar
  190. 190.
    Navadgi-Patil VM, Burgers PM (2008) Yeast DNA replication protein Dpb11 activates the Mec1/ATR checkpoint kinase. J Biol Chem 283(51):35853–35859PubMedCrossRefGoogle Scholar
  191. 191.
    Pfander B, Diffley JF (2011) Dpb11 coordinates Mec1 kinase activation with cell cycle-regulated Rad9 recruitment. EMBO J. doi: 10.1038/emboj.2011.345
  192. 192.
    Schwartz MF, Duong JK, Sun Z, Morrow JS, Pradhan D, Stern DF (2002) Rad9 phosphorylation sites couple Rad53 to the Saccharomyces cerevisiae DNA damage checkpoint. Mol Cell 9(5):1055–1065PubMedCrossRefGoogle Scholar
  193. 193.
    Emili A (1998) MEC1-dependent phosphorylation of Rad9p in response to DNA damage. Mol Cell 2(2):183–189PubMedCrossRefGoogle Scholar
  194. 194.
    Gilbert CS, van den Bosch M, Green CM, Vialard JE, Grenon M, Erdjument-Bromage H, Tempst P, Lowndes NF (2003) The budding yeast Rad9 checkpoint complex: chaperone proteins are required for its function. EMBO Rep 4(10):953–958PubMedCrossRefGoogle Scholar
  195. 195.
    Gilbert CS, Green CM, Lowndes NF (2001) Budding yeast Rad9 is an ATP-dependent Rad53 activating machine. Mol Cell 8(1):129–136PubMedCrossRefGoogle Scholar
  196. 196.
    Granata M, Lazzaro F, Novarina D, Panigada D, Puddu F, Abreu CM, Kumar R, Grenon M, Lowndes NF, Plevani P, Muzi-Falconi M (2010) Dynamics of Rad9 chromatin binding and checkpoint function are mediated by its dimerization and are cell cycle-regulated by CDK1 activity. PLoS Genet 6(8):e1001047Google Scholar
  197. 197.
    Grenon M, Costelloe T, Jimeno S, O’Shaughnessy A, Fitzgerald J, Zgheib O, Degerth L, Lowndes NF (2007) Docking onto chromatin via the Saccharomyces cerevisiae Rad9 Tudor domain. Yeast 24(2):105–119PubMedCrossRefGoogle Scholar
  198. 198.
    Huyen Y, Zgheib O, Ditullio RA Jr, Gorgoulis VG, Zacharatos P, Petty TJ, Sheston EA, Mellert HS, Stavridi ES, Halazonetis TD (2004) Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432(7015):406–411PubMedCrossRefGoogle Scholar
  199. 199.
    Puddu F, Granata M, Di Nola L, Balestrini A, Piergiovanni G, Lazzaro F, Giannattasio M, Plevani P, Muzi-Falconi M (2008) Phosphorylation of the budding yeast 9–1-1 complex is required for Dpb11 function in the full activation of the UV-induced DNA damage checkpoint. Mol Cell Biol 28(15):4782–4793PubMedCrossRefGoogle Scholar
  200. 200.
    van Leeuwen F, Gafken PR, Gottschling DE (2002) Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109(6):745–756PubMedCrossRefGoogle Scholar
  201. 201.
    Lacoste N, Utley RT, Hunter JM, Poirier GG, Cote J (2002) Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase. J Biol Chem 277(34):30421–30424PubMedCrossRefGoogle Scholar
  202. 202.
    Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389(6648):251–260PubMedCrossRefGoogle Scholar
  203. 203.
    Wysocki R, Javaheri A, Allard S, Sha F, Cote J, Kron SJ (2005) Role of dot1-dependent histone H3 methylation in G1 and S phase DNA damage checkpoint functions of Rad9. Mol Cell Biol 25(19):8430–8443PubMedCrossRefGoogle Scholar
  204. 204.
    Giannattasio M, Lazzaro F, Plevani P, Muzi-Falconi M (2005) The DNA damage checkpoint response requires histone H2B ubiquitination by Rad6-Bre1 and H3 methylation by Dot1. J Biol Chem 280(11):9879–9886PubMedCrossRefGoogle Scholar
  205. 205.
    Lancelot N, Charier G, Couprie J, Duband-Goulet I, Alpha-Bazin B, Quemeneur E, Ma E, Marsolier-Kergoat MC, Ropars V, Charbonnier JB, Miron S, Craescu CT, Callebaut I, Gilquin B, Zinn-Justin S (2007) The checkpoint Saccharomyces cerevisiae Rad9 protein contains a tandem tudor domain that recognizes DNA. Nucleic Acids Res 35(17):5898–5912PubMedCrossRefGoogle Scholar
  206. 206.
    Sweeney FD, Yang F, Chi A, Shabanowitz J, Hunt DF, Durocher D (2005) Saccharomyces cerevisiae Rad9 acts as a Mec1 adaptor to allow Rad53 activation. Curr Biol 15(15):1364–1375PubMedCrossRefGoogle Scholar
  207. 207.
    Du LL, Nakamura TM, Russell P (2006) Histone modification-dependent and -independent pathways for recruitment of checkpoint protein Crb2 to double-strand breaks. Genes Dev 20(12):1583–1596PubMedCrossRefGoogle Scholar
  208. 208.
    Sanders SL, Portoso M, Mata J, Bahler J, Allshire RC, Kouzarides T (2004) Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 119(5):603–614PubMedCrossRefGoogle Scholar
  209. 209.
    Fang J, Feng Q, Ketel CS, Wang H, Cao R, Xia L, Erdjument-Bromage H, Tempst P, Simon JA, Zhang Y (2002) Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr Biol 12(13):1086–1099PubMedCrossRefGoogle Scholar
  210. 210.
    Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y, Chuikov S, Valenzuela P, Tempst P, Steward R, Lis JT, Allis CD, Reinberg D (2002) PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell 9(6):1201–1213PubMedCrossRefGoogle Scholar
  211. 211.
    Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, Mer G (2006) Structural basis for the methylation state-specific recognition of histone H4–K20 by 53BP1 and Crb2 in DNA repair. Cell 127(7):1361–1373PubMedCrossRefGoogle Scholar
  212. 212.
    Greeson NT, Sengupta R, Arida AR, Jenuwein T, Sanders SL (2008) Di-methyl H4 lysine 20 targets the checkpoint protein Crb2 to sites of DNA damage. J Biol Chem 283(48):33168–33174PubMedCrossRefGoogle Scholar
  213. 213.
    Kilkenny ML, Dore AS, Roe SM, Nestoras K, Ho JC, Watts FZ, Pearl LH (2008) Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair. Genes Dev 22(15):2034–2047PubMedCrossRefGoogle Scholar
  214. 214.
    Nakamura TM, Du LL, Redon C, Russell P (2004) Histone H2A phosphorylation controls Crb2 recruitment at DNA breaks, maintains checkpoint arrest, and influences DNA repair in fission yeast. Mol Cell Biol 24(14):6215–6230PubMedCrossRefGoogle Scholar
  215. 215.
    Nakamura TM, Moser BA, Du LL, Russell P (2005) Cooperative control of Crb2 by ATM family and Cdc2 kinases is essential for the DNA damage checkpoint in fission yeast. Mol Cell Biol 25(24):10721–10730PubMedCrossRefGoogle Scholar
  216. 216.
    Furuya K, Poitelea M, Guo L, Caspari T, Carr AM (2004) Chk1 activation requires Rad9 S/TQ-site phosphorylation to promote association with C-terminal BRCT domains of Rad4TOPBP1. Genes Dev 18(10):1154–1164PubMedCrossRefGoogle Scholar
  217. 217.
    Saka Y, Esashi F, Matsusaka T, Mochida S, Yanagida M (1997) Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1. Genes Dev 11(24):3387–3400PubMedCrossRefGoogle Scholar
  218. 218.
    Mochida S, Esashi F, Aono N, Tamai K, O’Connell MJ, Yanagida M (2004) Regulation of checkpoint kinases through dynamic interaction with Crb2. EMBO J 23(2):418–428PubMedCrossRefGoogle Scholar
  219. 219.
    Wang H, Elledge SJ (2002) Genetic and physical interactions between DPB11 and DDC1 in the yeast DNA damage response pathway. Genetics 160(4):1295–1304PubMedGoogle Scholar
  220. 220.
    Germann SM, Oestergaard VH, Haas C, Salis P, Motegi A, Lisby M (2011) Dpb11/TopBP1 plays distinct roles in DNA replication, checkpoint response and homologous recombination. DNA Repair (Amst) 10(2):210–224. doi: 10.1016/j.dnarep.2010.11.001 CrossRefGoogle Scholar
  221. 221.
    Lee J, Dunphy WG (2010) Rad17 plays a central role in establishment of the interaction between TopBP1 and the Rad9-Hus1-Rad1 complex at stalled replication forks. Mol Biol Cell 21(6):926–935. doi: 10.1091/mbc.E09-11-0958 PubMedCrossRefGoogle Scholar
  222. 222.
    Albuquerque CP, Smolka MB, Payne SH, Bafna V, Eng J, Zhou H (2008) A multidimensional chromatography technology for in-depth phosphoproteome analysis. Mol Cell Proteomics 7(7):1389–1396PubMedCrossRefGoogle Scholar
  223. 223.
    Smolka MB, Albuquerque CP, Chen SH, Schmidt KH, Wei XX, Kolodner RD, Zhou H (2005) Dynamic changes in protein–protein interaction and protein phosphorylation probed with amine-reactive isotope tag. Mol Cell Proteomics 4(9):1358–1369PubMedCrossRefGoogle Scholar
  224. 224.
    Ward IM, Minn K, van Deursen J, Chen J (2003) p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Mol Cell Biol 23(7):2556–2563PubMedCrossRefGoogle Scholar
  225. 225.
    Wang B, Matsuoka S, Carpenter PB, Elledge SJ (2002) 53BP1, a mediator of the DNA damage checkpoint. Science 298(5597):1435–1438PubMedCrossRefGoogle Scholar
  226. 226.
    DiTullio RA Jr, Mochan TA, Venere M, Bartkova J, Sehested M, Bartek J, Halazonetis TD (2002) 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat Cell Biol 4(12):998–1002PubMedCrossRefGoogle Scholar
  227. 227.
    Wilson KA, Stern DF (2008) NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway. Cell Cycle 7(22):3584–3594PubMedCrossRefGoogle Scholar
  228. 228.
    Lee JH, Goodarzi AA, Jeggo PA, Paull TT (2010) 53BP1 promotes ATM activity through direct interactions with the MRN complex. EMBO J 29(3):574–585PubMedCrossRefGoogle Scholar
  229. 229.
    Pei H, Zhang L, Luo K, Qin Y, Chesi M, Fei F, Bergsagel PL, Wang L, You Z, Lou Z (2011) MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470(7332):124–128. doi: 10.1038/nature09658 PubMedCrossRefGoogle Scholar
  230. 230.
    Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ (2003) MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421(6926):961–966PubMedCrossRefGoogle Scholar
  231. 231.
    Xu X, Stern DF (2003) NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors. FASEB J 17(13):1842–1848. doi: 10.1096/fj.03-0310com PubMedCrossRefGoogle Scholar
  232. 232.
    Cotta-Ramusino C, McDonald ER 3rd, Hurov K, Sowa ME, Harper JW, Elledge SJ (2011) A DNA damage response screen identifies RHINO, a 9–1-1 and TopBP1 interacting protein required for ATR signaling. Science 332(6035):1313–1317. doi: 10.1126/science.1203430 PubMedCrossRefGoogle Scholar
  233. 233.
    Yamane K, Wu X, Chen J (2002) A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Mol Cell Biol 22(2):555–566PubMedCrossRefGoogle Scholar
  234. 234.
    Cescutti R, Negrini S, Kohzaki M, Halazonetis TD (2010) TopBP1 functions with 53BP1 in the G1 DNA damage checkpoint. EMBO J 29(21):3723–3732. doi: 10.1038/emboj.2010.238 PubMedCrossRefGoogle Scholar
  235. 235.
    Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP (2008) A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci USA 105(31):10762–10767PubMedCrossRefGoogle Scholar
  236. 236.
    Jowsey P, Morrice NA, Hastie CJ, McLauchlan H, Toth R, Rouse J (2007) Characterisation of the sites of DNA damage-induced 53BP1 phosphorylation catalysed by ATM and ATR. DNA Repair (Amst) 6(10):1536–1544CrossRefGoogle Scholar
  237. 237.
    Van Hoof D, Munoz J, Braam SR, Pinkse MW, Linding R, Heck AJ, Mummery CL, Krijgsveld J (2009) Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell 5(2):214–226PubMedCrossRefGoogle Scholar
  238. 238.
    Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127(3):635–648PubMedCrossRefGoogle Scholar
  239. 239.
    Stokes MP, Rush J, Macneill J, Ren JM, Sprott K, Nardone J, Yang V, Beausoleil SA, Gygi SP, Livingstone M, Zhang H, Polakiewicz RD, Comb MJ (2007) Profiling of UV-induced ATM/ATR signaling pathways. Proc Natl Acad Sci USA 104(50):19855–19860PubMedCrossRefGoogle Scholar
  240. 240.
    Molina H, Horn DM, Tang N, Mathivanan S, Pandey A (2007) Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry. Proc Natl Acad Sci USA 104(7):2199–2204PubMedCrossRefGoogle Scholar
  241. 241.
    Tao WA, Wollscheid B, O’Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R (2005) Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry. Nat Methods 2(8):591–598PubMedCrossRefGoogle Scholar
  242. 242.
    Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD, Gerke V, Schmidt-Arras DE, Berdel WE, Muller-Tidow C, Mann M, Serve H (2009) Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell 36(2):326–339. doi: 10.1016/j.molcel.2009.09.019 PubMedCrossRefGoogle Scholar
  243. 243.
    Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH (1996) BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res 56(14):3168–3172PubMedGoogle Scholar
  244. 244.
    Ruffner H, Verma IM (1997) BRCA1 is a cell cycle-regulated nuclear phosphoprotein. Proc Natl Acad Sci USA 94(14):7138–7143PubMedCrossRefGoogle Scholar
  245. 245.
    Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM (1999) BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Mol Cell Biol 19(7):4843–4854PubMedGoogle Scholar
  246. 246.
    Chi Y, Welcker M, Hizli AA, Posakony JJ, Aebersold R, Clurman BE (2008) Identification of CDK2 substrates in human cell lysates. Genome Biol 9(10):R149PubMedCrossRefGoogle Scholar
  247. 247.
    Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR 3rd (2008) Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis. J Proteome Res 7(3):1346–1351PubMedCrossRefGoogle Scholar
  248. 248.
    Sun Z, Hsiao J, Fay DS, Stern DF (1998) Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage checkpoint. Science 281(5374):272–274PubMedCrossRefGoogle Scholar
  249. 249.
    Durocher D, Henckel J, Fersht AR, Jackson SP (1999) The FHA domain is a modular phosphopeptide recognition motif. Mol Cell 4(3):387–394PubMedCrossRefGoogle Scholar
  250. 250.
    Schwartz MF, Lee S, Duong JK, Eminaga S, Stern DF (2003) FHA domain-mediated DNA checkpoint regulation of Rad53. Cell Cycle 2(4):384–396PubMedCrossRefGoogle Scholar
  251. 251.
    Smith J, Tho LM, Xu N, Gillespie DA (2010) The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res 108:73–112. doi: 10.1016/B978-0-12-380888-2.00003-0 PubMedCrossRefGoogle Scholar
  252. 252.
    Usui T, Foster SS, Petrini JH (2009) Maintenance of the DNA-damage checkpoint requires DNA-damage-induced mediator protein oligomerization. Mol Cell 33(2):147–159PubMedCrossRefGoogle Scholar
  253. 253.
    Blankley RT, Lydall D (2004) A domain of Rad9 specifically required for activation of Chk1 in budding yeast. J Cell Sci 117(Pt 4):601–608PubMedCrossRefGoogle Scholar
  254. 254.
    Uetz P, Giot L, Cagney G, Mansfield TA, Judson RS, Knight JR, Lockshon D, Narayan V, Srinivasan M, Pochart P, Qureshi-Emili A, Li Y, Godwin B, Conover D, Kalbfleisch T, Vijayadamodar G, Yang M, Johnston M, Fields S, Rothberg JM (2000) A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae. Nature 403(6770):623–627PubMedCrossRefGoogle Scholar
  255. 255.
    Chen Y, Caldwell JM, Pereira E, Baker RW, Sanchez Y (2009) ATRMec1 phosphorylation-independent activation of Chk1 in vivo. J Biol Chem 284(1):182–190PubMedCrossRefGoogle Scholar
  256. 256.
    Tapia-Alveal C, Calonge TM, O’Connell MJ (2009) Regulation of chk1. Cell Div 4:8PubMedCrossRefGoogle Scholar
  257. 257.
    Alcasabas AA, Osborn AJ, Bachant J, Hu F, Werler PJ, Bousset K, Furuya K, Diffley JF, Carr AM, Elledge SJ (2001) Mrc1 transduces signals of DNA replication stress to activate Rad53. Nat Cell Biol 3(11):958–965PubMedCrossRefGoogle Scholar
  258. 258.
    Foss EJ (2001) Tof1p regulates DNA damage responses during S phase in Saccharomyces cerevisiae. Genetics 157(2):567–577PubMedGoogle Scholar
  259. 259.
    Osborn AJ, Elledge SJ (2003) Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53. Genes Dev 17(14):1755–1767PubMedCrossRefGoogle Scholar
  260. 260.
    Smolka MB, Chen SH, Maddox PS, Enserink JM, Albuquerque CP, Wei XX, Desai A, Kolodner RD, Zhou H (2006) An FHA domain-mediated protein interaction network of Rad53 reveals its role in polarized cell growth. J Cell Biol 175(5):743–753PubMedCrossRefGoogle Scholar
  261. 261.
    Chen SH, Zhou H (2009) Reconstitution of Rad53 activation by Mec1 through adaptor protein Mrc1. J Biol Chem 284(28):18593–18604. doi: 10.1074/jbc.M109.018242 PubMedCrossRefGoogle Scholar
  262. 262.
    Katsuragi Y, Sagata N (2004) Regulation of Chk1 kinase by autoinhibition and ATR-mediated phosphorylation. Mol Biol Cell 15(4):1680–1689. doi: 10.1091/mbc.E03-12-0874 PubMedCrossRefGoogle Scholar
  263. 263.
    Oe T, Nakajo N, Katsuragi Y, Okazaki K, Sagata N (2001) Cytoplasmic occurrence of the Chk1/Cdc25 pathway and regulation of Chk1 in Xenopus oocytes. Dev Biol 229(1):250–261. doi: 10.1006/dbio.2000.9968 PubMedCrossRefGoogle Scholar
  264. 264.
    Chen P, Luo C, Deng Y, Ryan K, Register J, Margosiak S, Tempczyk-Russell A, Nguyen B, Myers P, Lundgren K, Kan CC, O’Connor PM, O’Connor PM (2000) The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation. Cell 100(6):681–692PubMedCrossRefGoogle Scholar
  265. 265.
    Walker M, Black EJ, Oehler V, Gillespie DA, Scott MT (2009) Chk1 C-terminal regulatory phosphorylation mediates checkpoint activation by de-repression of Chk1 catalytic activity. Oncogene 28(24):2314–2323. doi: 10.1038/onc.2009.102 PubMedCrossRefGoogle Scholar
  266. 266.
    Smits VA, Reaper PM, Jackson SP (2006) Rapid PIKK-dependent release of Chk1 from chromatin promotes the DNA-damage checkpoint response. Curr Biol 16(2):150–159. doi: 10.1016/j.cub.2005.11.066 PubMedCrossRefGoogle Scholar
  267. 267.
    Shimada M, Niida H, Zineldeen DH, Tagami H, Tanaka M, Saito H, Nakanishi M (2008) Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. Cell 132(2):221–232. doi: 10.1016/j.cell.2007.12.013 PubMedCrossRefGoogle Scholar
  268. 268.
    Falck J, Petrini JH, Williams BR, Lukas J, Bartek J (2002) The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat Genet 30(3):290–294. doi: 10.1038/ng845 PubMedCrossRefGoogle Scholar
  269. 269.
    Lee J, Kumagai A, Dunphy WG (2001) Positive regulation of Wee1 by Chk1 and 14–3-3 proteins. Mol Biol Cell 12(3):551–563PubMedGoogle Scholar
  270. 270.
    Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH (1999) A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr Biol 9(1):1–10PubMedCrossRefGoogle Scholar
  271. 271.
    Blasius M, Forment JV, Thakkar N, Wagner SA, Choudhary C, Jackson SP (2011) A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1. Genome Biol 12(8):R78. doi: 10.1186/gb-2011-12-8-r78 PubMedCrossRefGoogle Scholar
  272. 272.
    Sidorova JM, Breeden LL (1997) Rad53-dependent phosphorylation of Swi6 and down-regulation of CLN1 and CLN2 transcription occur in response to DNA damage in Saccharomyces cerevisiae. Genes Dev 11(22):3032–3045PubMedCrossRefGoogle Scholar
  273. 273.
    Sidorova JM, Breeden LL (2003) Rad53 checkpoint kinase phosphorylation site preference identified in the Swi6 protein of Saccharomyces cerevisiae. Mol Cell Biol 23(10):3405–3416PubMedCrossRefGoogle Scholar
  274. 274.
    Ghavidel A, Kislinger T, Pogoutse O, Sopko R, Jurisica I, Emili A (2007) Impaired tRNA nuclear export links DNA damage and cell-cycle checkpoint. Cell 131(5):915–926PubMedCrossRefGoogle Scholar
  275. 275.
    Schwob E, Bohm T, Mendenhall MD, Nasmyth K (1994) The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Cell 79(2):233–244PubMedCrossRefGoogle Scholar
  276. 276.
    Verma R, Annan RS, Huddleston MJ, Carr SA, Reynard G, Deshaies RJ (1997) Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase. Science 278(5337):455–460PubMedCrossRefGoogle Scholar
  277. 277.
    Nyberg KA, Michelson RJ, Putnam CW, Weinert TA (2002) Toward maintaining the genome: DNA damage and replication checkpoints. Annu Rev Genet 36:617–656PubMedCrossRefGoogle Scholar
  278. 278.
    Ahn JY, Schwarz JK, Piwnica-Worms H, Canman CE (2000) Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. Cancer Res 60(21):5934–5936PubMedGoogle Scholar
  279. 279.
    Ahn JY, Li X, Davis HL, Canman CE (2002) Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain. J Biol Chem 277(22):19389–19395. doi: 10.1074/jbc.M200822200 PubMedCrossRefGoogle Scholar
  280. 280.
    Oliver AW, Paul A, Boxall KJ, Barrie SE, Aherne GW, Garrett MD, Mittnacht S, Pearl LH (2006) Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange. EMBO J 25(13):3179–3190. doi: 10.1038/sj.emboj.7601209 PubMedCrossRefGoogle Scholar
  281. 281.
    Mailand N, Falck J, Lukas C, Syljuasen RG, Welcker M, Bartek J, Lukas J (2000) Rapid destruction of human Cdc25A in response to DNA damage. Science 288(5470):1425–1429PubMedCrossRefGoogle Scholar
  282. 282.
    Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410(6830):842–847. doi: 10.1038/35071124 PubMedCrossRefGoogle Scholar
  283. 283.
    Hoffmann I, Draetta G, Karsenti E (1994) Activation of the phosphatase activity of human cdc25A by a cdk2-cyclin E dependent phosphorylation at the G1/S transition. EMBO J 13(18):4302–4310PubMedGoogle Scholar
  284. 284.
    Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281(5383):1677–1679PubMedCrossRefGoogle Scholar
  285. 285.
    Dumaz N, Meek DW (1999) Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO J 18(24):7002–7010. doi: 10.1093/emboj/18.24.7002 PubMedCrossRefGoogle Scholar
  286. 286.
    Chehab NH, Malikzay A, Appel M, Halazonetis TD (2000) Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev 14(3):278–288PubMedGoogle Scholar
  287. 287.
    Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14(3):289–300PubMedGoogle Scholar
  288. 288.
    Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630):296–299. doi: 10.1038/387296a0 PubMedCrossRefGoogle Scholar
  289. 289.
    Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287(5459):1824–1827PubMedCrossRefGoogle Scholar
  290. 290.
    Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D (1999) Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci USA 96(26):14973–14977PubMedCrossRefGoogle Scholar
  291. 291.
    Chen L, Gilkes DM, Pan Y, Lane WS, Chen J (2005) ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J 24(19):3411–3422. doi: 10.1038/sj.emboj.7600812 PubMedCrossRefGoogle Scholar
  292. 292.
    Zhang Y, Xiong Y (2001) A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 292(5523):1910–1915. doi: 10.1126/science.1058637 PubMedCrossRefGoogle Scholar
  293. 293.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512PubMedCrossRefGoogle Scholar
  294. 294.
    Ekholm SV, Reed SI (2000) Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol 12(6):676–684PubMedCrossRefGoogle Scholar
  295. 295.
    Segurado M, Tercero JA (2009) The S-phase checkpoint: targeting the replication fork. Biol Cell 101(11):617–627. doi: 10.1042/BC20090053 PubMedCrossRefGoogle Scholar
  296. 296.
    Zegerman P, Diffley JF (2009) DNA replication as a target of the DNA damage checkpoint. DNA Repair (Amst) 8(9):1077–1088CrossRefGoogle Scholar
  297. 297.
    Myung K, Kolodner RD (2002) Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 99(7):4500–4507PubMedCrossRefGoogle Scholar
  298. 298.
    Puddu F, Piergiovanni G, Plevani P, Muzi-Falconi M (2011) Sensing of replication stress and Mec1 activation act through two independent pathways involving the 9-1-1 complex and DNA polymerase epsilon. PLoS Genet 7(3):e1002022. doi: 10.1371/journal.pgen.1002022
  299. 299.
    Paulovich AG, Margulies RU, Garvik BM, Hartwell LH (1997) RAD9, RAD17, and RAD24 are required for S phase regulation in Saccharomyces cerevisiae in response to DNA damage. Genetics 145(1):45–62PubMedGoogle Scholar
  300. 300.
    Tercero JA, Diffley JF (2001) Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412(6846):553–557PubMedCrossRefGoogle Scholar
  301. 301.
    Tercero JA, Longhese MP, Diffley JF (2003) A central role for DNA replication forks in checkpoint activation and response. Mol Cell 11(5):1323–1336PubMedCrossRefGoogle Scholar
  302. 302.
    Lopes M, Cotta-Ramusino C, Pellicioli A, Liberi G, Plevani P, Muzi-Falconi M, Newlon CS, Foiani M (2001) The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412(6846):557–561PubMedCrossRefGoogle Scholar
  303. 303.
    Santocanale C, Diffley JF (1998) A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 395(6702):615–618PubMedCrossRefGoogle Scholar
  304. 304.
    Shirahige K, Hori Y, Shiraishi K, Yamashita M, Takahashi K, Obuse C, Tsurimoto T, Yoshikawa H (1998) Regulation of DNA-replication origins during cell-cycle progression. Nature 395(6702):618–621PubMedCrossRefGoogle Scholar
  305. 305.
    Allen JB, Zhou Z, Siede W, Friedberg EC, Elledge SJ (1994) The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast. Genes Dev 8(20):2401–2415PubMedCrossRefGoogle Scholar
  306. 306.
    Longhese MP, Neecke H, Paciotti V, Lucchini G, Plevani P (1996) The 70 kDa subunit of replication protein A is required for the G1/S and intra-S DNA damage checkpoints in budding yeast. Nucleic Acids Res 24(18):3533–3537PubMedCrossRefGoogle Scholar
  307. 307.
    Brush GS, Morrow DM, Hieter P, Kelly TJ (1996) The ATM homologue MEC1 is required for phosphorylation of replication protein A in yeast. Proc Natl Acad Sci USA 93(26):15075–15080PubMedCrossRefGoogle Scholar
  308. 308.
    Marini F, Pellicioli A, Paciotti V, Lucchini G, Plevani P, Stern DF, Foiani M (1997) A role for DNA primase in coupling DNA replication to DNA damage response. EMBO J 16(3):639–650PubMedCrossRefGoogle Scholar
  309. 309.
    Longhese MP, Fraschini R, Plevani P, Lucchini G (1996) Yeast pip3/mec3 mutants fail to delay entry into S phase and to slow DNA replication in response to DNA damage, and they define a functional link between Mec3 and DNA primase. Mol Cell Biol 16(7):3235–3244PubMedGoogle Scholar
  310. 310.
    Navas TA, Zhou Z, Elledge SJ (1995) DNA polymerase epsilon links the DNA replication machinery to the S phase checkpoint. Cell 80(1):29–39PubMedCrossRefGoogle Scholar
  311. 311.
    Lou H, Komata M, Katou Y, Guan Z, Reis CC, Budd M, Shirahige K, Campbell JL (2008) Mrc1 and DNA polymerase epsilon function together in linking DNA replication and the S phase checkpoint. Mol Cell 32(1):106–117PubMedCrossRefGoogle Scholar
  312. 312.
    Labib K (2010) How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells? Genes Dev 24(12):1208–1219. doi: 10.1101/gad.1933010 PubMedCrossRefGoogle Scholar
  313. 313.
    Lopez-Mosqueda J, Maas NL, Jonsson ZO, Defazio-Eli LG, Wohlschlegel J, Toczyski DP (2010) Damage-induced phosphorylation of Sld3 is important to block late origin firing. Nature 467(7314):479–483. doi: 10.1038/nature09377 PubMedCrossRefGoogle Scholar
  314. 314.
    Zegerman P, Diffley JF (2010) Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation. Nature 467(7314):474–478. doi: 10.1038/nature09373 PubMedCrossRefGoogle Scholar
  315. 315.
    Tanaka S, Umemori T, Hirai K, Muramatsu S, Kamimura Y, Araki H (2007) CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature 445(7125):328–332PubMedCrossRefGoogle Scholar
  316. 316.
    Zegerman P, Diffley JF (2007) Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature 445(7125):281–285PubMedCrossRefGoogle Scholar
  317. 317.
    Segurado M, Diffley JF (2008) Separate roles for the DNA damage checkpoint protein kinases in stabilizing DNA replication forks. Genes Dev 22(13):1816–1827PubMedCrossRefGoogle Scholar
  318. 318.
    Morin I, Ngo HP, Greenall A, Zubko MK, Morrice N, Lydall D (2008) Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response. EMBO J 27(18):2400–2410PubMedCrossRefGoogle Scholar
  319. 319.
    Cotta-Ramusino C, Fachinetti D, Lucca C, Doksani Y, Lopes M, Sogo J, Foiani M (2005) Exo1 processes stalled replication forks and counteracts fork reversal in checkpoint-defective cells. Mol Cell 17(1):153–159PubMedCrossRefGoogle Scholar
  320. 320.
    Smolka MB, Albuquerque CP, Chen SH, Zhou H (2007) Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases. Proc Natl Acad Sci USA 104(25):10364–10369PubMedCrossRefGoogle Scholar
  321. 321.
    de la Torre Ruiz MA, Lowndes NF (2000) DUN1 defines one branch downstream of RAD53 for transcription and DNA damage repair in Saccharomyces cerevisiae. FEBS Lett 485(2–3):205–206PubMedCrossRefGoogle Scholar
  322. 322.
    Zhou Z, Elledge SJ (1993) DUN1 encodes a protein kinase that controls the DNA damage response in yeast. Cell 75(6):1119–1127PubMedCrossRefGoogle Scholar
  323. 323.
    Chen SH, Smolka MB, Zhou H (2007) Mechanism of Dun1 activation by Rad53 phosphorylation in Saccharomyces cerevisiae. J Biol Chem 282(2):986–995PubMedCrossRefGoogle Scholar
  324. 324.
    Huang M, Zhou Z, Elledge SJ (1998) The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor. Cell 94(5):595–605PubMedCrossRefGoogle Scholar
  325. 325.
    Zhao X, Rothstein R (2002) The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1. Proc Natl Acad Sci USA 99(6):3746–3751PubMedCrossRefGoogle Scholar
  326. 326.
    Lee YD, Wang J, Stubbe J, Elledge SJ (2008) Dif1 is a DNA-damage-regulated facilitator of nuclear import for ribonucleotide reductase. Mol Cell 32(1):70–80PubMedCrossRefGoogle Scholar
  327. 327.
    Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616–627PubMedCrossRefGoogle Scholar
  328. 328.
    Zachos G, Rainey MD, Gillespie DA (2005) Chk1-dependent S-M checkpoint delay in vertebrate cells is linked to maintenance of viable replication structures. Mol Cell Biol 25(2):563–574. doi: 10.1128/MCB.25.2.563-574.2005 PubMedCrossRefGoogle Scholar
  329. 329.
    Zachos G, Rainey MD, Gillespie DA (2003) Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects. EMBO J 22(3):713–723. doi: 10.1093/emboj/cdg060 PubMedCrossRefGoogle Scholar
  330. 330.
    Trenz K, Smith E, Smith S, Costanzo V (2006) ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks. EMBO J 25(8):1764–1774. doi: 10.1038/sj.emboj.7601045 PubMedCrossRefGoogle Scholar
  331. 331.
    Grallert B, Boye E (2008) The multiple facets of the intra-S checkpoint. Cell Cycle 7(15):2315–2320PubMedGoogle Scholar
  332. 332.
    Lee J, Kumagai A, Dunphy WG (2003) Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, Rad17. Mol Cell 11(2):329–340PubMedCrossRefGoogle Scholar
  333. 333.
    Guo Z, Kumagai A, Wang SX, Dunphy WG (2000) Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev 14(21):2745–2756PubMedCrossRefGoogle Scholar
  334. 334.
    Kumagai A, Dunphy WG (2000) Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts. Mol Cell 6(4):839–849PubMedCrossRefGoogle Scholar
  335. 335.
    Chini CC, Chen J (2003) Human claspin is required for replication checkpoint control. J Biol Chem 278(32):30057–30062. doi: 10.1074/jbc.M301136200 PubMedCrossRefGoogle Scholar
  336. 336.
    Gotter AL, Suppa C, Emanuel BS (2007) Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. J Mol Biol 366(1):36–52. doi: 10.1016/j.jmb.2006.10.097 PubMedCrossRefGoogle Scholar
  337. 337.
    Unsal-Kacmaz K, Chastain PD, Qu PP, Minoo P, Cordeiro-Stone M, Sancar A, Kaufmann WK (2007) The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Mol Cell Biol 27(8):3131–3142. doi: 10.1128/MCB.02190-06 PubMedCrossRefGoogle Scholar
  338. 338.
    Unsal-Kacmaz K, Mullen TE, Kaufmann WK, Sancar A (2005) Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol 25(8):3109–3116. doi: 10.1128/MCB.25.8.3109-3116.2005 PubMedCrossRefGoogle Scholar
  339. 339.
    Kemp MG, Akan Z, Yilmaz S, Grillo M, Smith-Roe SL, Kang TH, Cordeiro-Stone M, Kaufmann WK, Abraham RT, Sancar A, Unsal-Kacmaz K (2010) Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress. J Biol Chem 285(22):16562–16571. doi: 10.1074/jbc.M110.110304 PubMedCrossRefGoogle Scholar
  340. 340.
    Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ (1997) Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277(5331):1497–1501PubMedCrossRefGoogle Scholar
  341. 341.
    Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H (1997) Mitotic and G2 checkpoint control: regulation of 14–3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277(5331):1501–1505PubMedCrossRefGoogle Scholar
  342. 342.
    Sorensen CS, Syljuasen RG, FalckSchroeder J, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J (2003) Chk1 regulates the S phase checkpoint by coupling the physiological turnover, ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 3(3):247–258PubMedCrossRefGoogle Scholar
  343. 343.
    Liu P, Barkley LR, Day T, Bi X, Slater DM, Alexandrow MG, Nasheuer HP, Vaziri C (2006) The Chk1-mediated S-phase checkpoint targets initiation factor Cdc45 via a Cdc25A/Cdk2-independent mechanism. J Biol Chem 281(41):30631–30644. doi: 10.1074/jbc.M602982200 PubMedCrossRefGoogle Scholar
  344. 344.
    Kim ST, Xu B, Kastan MB (2002) Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev 16(5):560–570. doi: 10.1101/gad.970602 PubMedCrossRefGoogle Scholar
  345. 345.
    Yazdi PT, Wang Y, Zhao S, Patel N, Lee EY, Qin J (2002) SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. Genes Dev 16(5):571–582. doi: 10.1101/gad.970702 PubMedCrossRefGoogle Scholar
  346. 346.
    Kitagawa R, Bakkenist CJ, McKinnon PJ, Kastan MB (2004) Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway. Genes Dev 18(12):1423–1438. doi: 10.1101/gad.1200304 PubMedCrossRefGoogle Scholar
  347. 347.
    Luo H, Li Y, Mu JJ, Zhang J, Tonaka T, Hamamori Y, Jung SY, Wang Y, Qin J (2008) Regulation of intra-S phase checkpoint by ionizing radiation (IR)-dependent and IR-independent phosphorylation of SMC3. J Biol Chem 283(28):19176–19183. doi: 10.1074/jbc.M802299200 PubMedCrossRefGoogle Scholar
  348. 348.
    Norbury C, Blow J, Nurse P (1991) Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J 10(11):3321–3329PubMedGoogle Scholar
  349. 349.
    Krek W, Nigg EA (1991) Differential phosphorylation of vertebrate p34cdc2 kinase at the G1/S and G2/M transitions of the cell cycle: identification of major phosphorylation sites. EMBO J 10(2):305–316PubMedGoogle Scholar
  350. 350.
    Gould KL, Nurse P (1989) Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342(6245):39–45. doi: 10.1038/342039a0 PubMedCrossRefGoogle Scholar
  351. 351.
    Lee MS, Enoch T, Piwnica-Worms H (1994) mik1 + encodes a tyrosine kinase that phosphorylates p34cdc2 on tyrosine 15. J Biol Chem 269(48):30530–30537PubMedGoogle Scholar
  352. 352.
    Parker LL, Atherton-Fessler S, Piwnica-Worms H (1992) p107wee1 is a dual-specificity kinase that phosphorylates p34cdc2 on tyrosine 15. Proc Natl Acad Sci USA 89(7):2917–2921PubMedCrossRefGoogle Scholar
  353. 353.
    Den Haese GJ, Walworth N, Carr AM, Gould KL (1995) The Wee1 protein kinase regulates T14 phosphorylation of fission yeast Cdc2. Mol Biol Cell 6(4):371–385Google Scholar
  354. 354.
    Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85. doi: 10.1146/annurev.biochem.73.011303.073723 PubMedCrossRefGoogle Scholar
  355. 355.
    Raleigh JM, O’Connell MJ (2000) The G(2) DNA damage checkpoint targets both Wee1 and Cdc25. J Cell Sci 113(Pt 10):1727–1736PubMedGoogle Scholar
  356. 356.
    O’Connell MJ, Raleigh JM, Verkade HM, Nurse P (1997) Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. EMBO J 16(3):545–554PubMedCrossRefGoogle Scholar
  357. 357.
    Rhind N, Furnari B, Russell P (1997) Cdc2 tyrosine phosphorylation is required for the DNA damage checkpoint in fission yeast. Genes Dev 11(4):504–511PubMedCrossRefGoogle Scholar
  358. 358.
    Zeng Y, Piwnica-Worms H (1999) DNA damage and replication checkpoints in fission yeast require nuclear exclusion of the Cdc25 phosphatase via 14–3-3 binding. Mol Cell Biol 19(11):7410–7419PubMedGoogle Scholar
  359. 359.
    Zeng Y, Forbes KC, Wu Z, Moreno S, Piwnica-Worms H, Enoch T (1998) Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1. Nature 395(6701):507–510PubMedCrossRefGoogle Scholar
  360. 360.
    Lopez-Girona A, Furnari B, Mondesert O, Russell P (1999) Nuclear localization of Cdc25 is regulated by DNA damage and a 14–3-3 protein. Nature 397(6715):172–175PubMedCrossRefGoogle Scholar
  361. 361.
    Amon A, Surana U, Muroff I, Nasmyth K (1992) Regulation of p34CDC28 tyrosine phosphorylation is not required for entry into mitosis in S. cerevisiae. Nature 355(6358):368–371PubMedCrossRefGoogle Scholar
  362. 362.
    Sorger PK, Murray AW (1992) S-phase feedback control in budding yeast independent of tyrosine phosphorylation of p34cdc28. Nature 355(6358):365–368PubMedCrossRefGoogle Scholar
  363. 363.
    Cohen-Fix O, Koshland D (1997) The metaphase-to-anaphase transition: avoiding a mid-life crisis. Curr Opin Cell Biol 9(6):800–806PubMedCrossRefGoogle Scholar
  364. 364.
    Gardner R, Putnam CW, Weinert T (1999) RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast. EMBO J 18(11):3173–3185PubMedCrossRefGoogle Scholar
  365. 365.
    Liang F, Wang Y (2007) DNA damage checkpoints inhibit mitotic exit by two different mechanisms. Mol Cell Biol 27(14):5067–5078PubMedCrossRefGoogle Scholar
  366. 366.
    Ciosk R, Zachariae W, Michaelis C, Shevchenko A, Mann M, Nasmyth K (1998) An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 93(6):1067–1076PubMedCrossRefGoogle Scholar
  367. 367.
    Wang H, Liu D, Wang Y, Qin J, Elledge SJ (2001) Pds1 phosphorylation in response to DNA damage is essential for its DNA damage checkpoint function. Genes Dev 15(11):1361–1372PubMedCrossRefGoogle Scholar
  368. 368.
    Agarwal R, Tang Z, Yu H, Cohen-Fix O (2003) Two distinct pathways for inhibiting pds1 ubiquitination in response to DNA damage. J Biol Chem 278(45):45027–45033PubMedCrossRefGoogle Scholar
  369. 369.
    Charles JF, Jaspersen SL, Tinker-Kulberg RL, Hwang L, Szidon A, Morgan DO (1998) The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin destruction machinery in S. cerevisiae. Curr Biol 8(9):497–507PubMedCrossRefGoogle Scholar
  370. 370.
    Shirayama M, Zachariae W, Ciosk R, Nasmyth K (1998) The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae. EMBO J 17(5):1336–1349PubMedCrossRefGoogle Scholar
  371. 371.
    Schleker T, Shimada K, Sack R, Pike BL, Gasser SM (2010) Cell cycle-dependent phosphorylation of Rad53 kinase by Cdc5 and Cdc28 modulates checkpoint adaptation. Cell Cycle 9(2):350–363PubMedCrossRefGoogle Scholar
  372. 372.
    Vidanes GM, Sweeney FD, Galicia S, Cheung S, Doyle JP, Durocher D, Toczyski DP (2010) CDC5 inhibits the hyperphosphorylation of the checkpoint kinase Rad53, leading to checkpoint adaptation. PLoS Biol 8(1):e1000286PubMedCrossRefGoogle Scholar
  373. 373.
    Donnianni RA, Ferrari M, Lazzaro F, Clerici M, Tamilselvan Nachimuthu B, Plevani P, Muzi-Falconi M, Pellicioli A (2010) Elevated levels of the polo kinase Cdc5 override the Mec1/ATR checkpoint in budding yeast by acting at different steps of the signaling pathway. PLoS Genet 6(1):e1000763PubMedCrossRefGoogle Scholar
  374. 374.
    Cheng L, Hunke L, Hardy CF (1998) Cell cycle regulation of the Saccharomyces cerevisiae polo-like kinase cdc5p. Mol Cell Biol 18(12):7360–7370PubMedGoogle Scholar
  375. 375.
    Ferreira MG, Cooper JP (2004) Two modes of DNA double-strand break repair are reciprocally regulated through the fission yeast cell cycle. Genes Dev 18(18):2249–2254PubMedCrossRefGoogle Scholar
  376. 376.
    Zhang Y, Shim EY, Davis M, Lee SE (2009) Regulation of repair choice: Cdk1 suppresses recruitment of end joining factors at DNA breaks. DNA Repair (Amst) 8(10):1235–1241CrossRefGoogle Scholar
  377. 377.
    Bensimon A, Schmidt A, Ziv Y, Elkon R, Wang SY, Chen DJ, Aebersold R, Shiloh Y (2010) ATM-dependent and -independent dynamics of the nuclear phosphoproteome after DNA damage. Sci Signal 3(151):rs3. doi: 10.1126/scisignal.2001034
  378. 378.
    Bennetzen MV, Larsen DH, Bunkenborg J, Bartek J, Lukas J, Andersen JS (2010) Site-specific phosphorylation dynamics of the nuclear proteome during the DNA damage response. Mol Cell Proteomics 9(6):1314–1323. doi: 10.1074/mcp.M900616-MCP200 PubMedCrossRefGoogle Scholar
  379. 379.
    van Kouwenhove M, Kedde M, Agami R (2011) MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 11(9):644–656. doi: 10.1038/nrc3107 PubMedCrossRefGoogle Scholar
  380. 380.
    Wouters MD, van Gent DC, Hoeijmakers JH, Pothof J (2011) MicroRNAs, the DNA damage response and cancer. Mutat Res. doi: 10.1016/j.mrfmmm.2011.03.012
  381. 381.
    Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 39(5):673–677. doi: 10.1038/ng2003 PubMedCrossRefGoogle Scholar
  382. 382.
    Pothof J, Verkaik NS, van IW, Wiemer EA, Ta VT, van der Horst GT, Jaspers NG, van Gent DC, Persengiev SP (2009) MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response. EMBO J 28(14):2090–2099. doi: 10.1038/emboj.2009.156 PubMedCrossRefGoogle Scholar
  383. 383.
    Bu Y, Lu C, Bian C, Wang J, Li J, Zhang B, Li Z, Brewer G, Zhao RC (2009) Knockdown of Dicer in MCF-7 human breast carcinoma cells results in G1 arrest and increased sensitivity to cisplatin. Oncol Rep 21(1):13–17PubMedGoogle Scholar
  384. 384.
    Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D (2011) miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell 41(2):210–220. doi: 10.1016/j.molcel.2010.12.005 PubMedCrossRefGoogle Scholar
  385. 385.
    Dimitrova N, Chen YC, Spector DL, de Lange T (2008) 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 456(7221):524–528PubMedCrossRefGoogle Scholar
  386. 386.
    Difilippantonio S, Gapud E, Wong N, Huang CY, Mahowald G, Chen HT, Kruhlak MJ, Callen E, Livak F, Nussenzweig MC, Sleckman BP, Nussenzweig A (2008) 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456(7221):529–533PubMedCrossRefGoogle Scholar
  387. 387.
    Noon AT, Shibata A, Rief N, Lobrich M, Stewart GS, Jeggo PA, Goodarzi AA (2010) 53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair. Nat Cell Biol 12(2):177–184. doi: 10.1038/ncb2017 PubMedCrossRefGoogle Scholar
  388. 388.
    Zhu Q, Pao GM, Huynh AM, Suh H, Tonnu N, Nederlof PM, Gage FH, Verma IM (2011) BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 477(7363):179–184. doi: 10.1038/nature10371 PubMedCrossRefGoogle Scholar
  389. 389.
    Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S (2009) Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460(7259):1132–1135. doi: 10.1038/nature08235 PubMedCrossRefGoogle Scholar
  390. 390.
    Li H, Collado M, Villasante A, Strati K, Ortega S, Canamero M, Blasco MA, Serrano M (2009) The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460(7259):1136–1139. doi: 10.1038/nature08290 PubMedCrossRefGoogle Scholar
  391. 391.
    Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Belmonte JC (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460(7259):1140–1144. doi: 10.1038/nature08311 PubMedCrossRefGoogle Scholar
  392. 392.
    Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG, Hochedlinger K (2009) Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460(7259):1145–1148. doi: 10.1038/nature08285 PubMedCrossRefGoogle Scholar
  393. 393.
    Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460(7259):1149–1153. doi: 10.1038/nature08287 PubMedCrossRefGoogle Scholar
  394. 394.
    Andang M, Hjerling-Leffler J, Moliner A, Lundgren TK, Castelo-Branco G, Nanou E, Pozas E, Bryja V, Halliez S, Nishimaru H, Wilbertz J, Arenas E, Koltzenburg M, Charnay P, El Manira A, Ibanez CF, Ernfors P (2008) Histone H2AX-dependent GABA(A) receptor regulation of stem cell proliferation. Nature 451(7177):460–464. doi: 10.1038/nature06488 PubMedCrossRefGoogle Scholar

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© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural SciencesNational University of Ireland GalwayGalwayIreland

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